◈

Mechanistic Hypotheses

2

Choroid Plexus CSF Hypersecretion (Metabolic-Hormonal) Model

choroid_plexus_csf_hypersecretion EMERGING

A converging working model places obesity-associated metabolic and hormonal dysregulation upstream of choroid plexus cerebrospinal fluid hypersecretion as the primary driver of raised intracranial pressure. Visceral adiposity is proposed to elevate adipose 11-beta-hydroxysteroid dehydrogenase type 1 activity and circulating androgens, and obesity-associated GLP-1 signaling is proposed to act on choroid plexus epithelium, together stimulating choroid plexus Na+/K+-ATPase-driven CSF secretion. Pharmacological proof-of-concept from 11-beta-HSD1 inhibition and GLP-1 receptor agonism reducing intracranial pressure has driven interest in this model, and on this view transverse sinus stenosis is an amplifying feedback consequence of raised pressure rather than the initiating lesion.

Status EMERGING rather than CANONICAL because the human evidence linking specific hormonal axes to choroid plexus secretion is still maturing. A dedicated Choroid plexus CSF hypersecretion pathophysiology node now represents the secretory arm anchored on the AZD4017 (11-beta-HSD1) and exenatide (GLP-1) randomized trials, but the 11-beta-HSD1 trial did not meet its primary endpoint, so the upstream hormonal mechanism remains a working model rather than established causation.

Pathograph links

Choroid plexus CSF hypersecretion -> Dysregulated cerebrospinal fluid dynamics Excess choroid plexus CSF secretion is the secretory component of dysregulated CSF dynamics.

Choroid plexus CSF hypersecretion -> Elevated intracranial pressure Increased CSF secretion raises CSF volume and contributes directly to sustained elevation of intracranial pressure.

Deep research

OpenScientist citations 41 citations 2026-06-04T08:50:25.512404

Show evidence (1 reference)

PMID:34929642 SUPPORT Other

"recent studies highlighting the pathogenic role of metabolic and hormonal factors have led to the identification of several pharmacological targets and development of novel therapeutic agents"

This supports a metabolic-hormonal driver upstream of CSF dynamics and the emergence of targeted pharmacological therapies consistent with the choroid plexus hypersecretion model.

Primary Venous Sinus Obstruction Model

primary_venous_sinus_obstruction ALTERNATIVE

An alternative model proposes transverse/sigmoid venous sinus stenosis as the initiating lesion: elevated dural venous sinus pressure impairs CSF absorption at the arachnoid granulations and raises intracranial pressure. The cause-versus-consequence relationship between sinus stenosis and raised pressure is not fully resolved, since stenosis frequently reverses after pressure is lowered; many authors now regard it as an amplifying feedback loop rather than the primary cause, though venous sinus stenting benefits a subset of patients.

Show evidence (1 reference)

PMID:34929642 PARTIAL Other

"The pathophysiology involves dysregulation of cerebrospinal fluid (CSF) dynamics and venous sinus pressure"

Venous sinus pressure is recognized as part of IIH pathophysiology, but the review frames it alongside CSF dynamics rather than as the established primary cause, consistent with an alternative/contributory rather than canonical role.

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Discussions and Knowledge Gaps

4

What is the proximate mechanism of headache in IIH, and why is it imperfectly coupled to the degree of intracranial pressure elevation?

KNOWLEDGE GAP OPEN gap_iih_headache_mechanism

Attached to

pathophysiology#Headache syndrome pathophysiology#CGRP-mediated trigeminovascular headache signaling

Headache is the dominant symptomatic morbidity but its mechanism is only partly understood. Human CGRP provocation data now support trigeminovascular neuropeptide signaling and ICP pulsatility as a proximal mechanism, while headache can still persist or fluctuate independently of measured pressure. Modeling headache purely as a downstream consequence of raised mean pressure remains incomplete.

Is transverse venous sinus stenosis a primary initiating lesion or a pressure-dependent feedback consequence in IIH?

KNOWLEDGE GAP OPEN gap_iih_venous_stenosis_cause_or_consequence

Attached to

pathophysiology#Venous sinus stenosis and intracranial venous hypertension pathophysiology#Dysregulated cerebrospinal fluid dynamics pathophysiology#Elevated intracranial pressure

Transverse sinus stenosis is present in most patients and venous sinus stenting helps a subset, yet stenosis can reverse once intracranial pressure is lowered. Whether it initiates the disease or amplifies an already-elevated-pressure state is unresolved and distinguishes the primary venous obstruction model from the choroid plexus hypersecretion model.

Why does IIH predominantly affect obese women of reproductive age, and what distinguishes the mechanism in non-obese or atypical cases?

KNOWLEDGE GAP OPEN gap_iih_sex_and_nonobese_predilection

Attached to

pathophysiology#Metabolic risk background pathophysiology#Choroid plexus CSF hypersecretion

The strong predilection for obese women of reproductive age implicates sex hormone modulation of choroid plexus secretory capacity, but the responsible axis is not fully characterized. A minority of patients are non-obese, suggesting a distinct or additional primary mechanism (e.g., medication exposure or venous anomaly) that the current metabolic-background node does not yet capture.

How do obesity/metabolic-hormonal drivers, venous sinus pressure and stenosis, and CSF production/absorption interact causally in IIH, and which of these is the initiating event versus an amplifying feedback consequence?

KNOWLEDGE GAP OPEN gap_iih_obesity_venous_csf_hierarchy

Attached to

pathophysiology#Metabolic risk background pathophysiology#Choroid plexus CSF hypersecretion pathophysiology#Venous sinus stenosis and intracranial venous hypertension pathophysiology#Dysregulated cerebrospinal fluid dynamics

IIH is defined by raised intracranial pressure without a mass lesion, yet the causal ordering among its candidate mechanisms remains unresolved. Multiple pathways have been proposed as the underlying cause - choroid plexus CSF overproduction, impaired CSF outflow/absorption, elevated venous sinus pressure with transverse sinus stenosis, glymphatic dysfunction, and obesity-associated hormonal alterations - but no single theory explains the entire clinical picture. The metabolic-hormonal arm is an attractive upstream driver because pharmacological modulation lowers intracranial pressure, yet the AZD4017 trial missed its primary endpoint and the human evidence linking specific hormonal axes to choroid plexus secretion is still maturing. Venous sinus stenosis is present in most patients and stenting helps a subset, but stenosis frequently reverses once pressure is lowered, so it may amplify rather than initiate the disease via a positive feedback loop. There is even emerging argument that CSF overproduction is unlikely to be the primary driver and that carbonic-anhydrase inhibition targets a consequence rather than the cause. Disentangling which node is initiating versus secondary across obese, non-obese, and atypical patients is the central unresolved question and would reorder the entire pathophysiology DAG and its therapeutic targets.

Proposed experiments

Interventional perturbation cohort to order metabolic, venous, and CSF mechanisms

prospective interventional mechanistic cohort study

exp_iih_mechanism_perturbation_ordering

Enroll newly diagnosed IIH patients (obese and non-obese strata) and apply mechanism-specific perturbations with simultaneous multi-axis monitoring.

Readouts

Metabolic-hormonal response and intracranial pressure

pathophysiology#Metabolic risk background

Quantify circulating metabolic and hormonal markers and body composition alongside intracranial pressure during a metabolic-hormonal intervention.

serum hormone quantification lumbar puncture opening pressure measurement

Direction: NEGATIVE

CSF secretion response to carbonic anhydrase inhibition

pathophysiology#Choroid plexus CSF hypersecretion

Measure intracranial pressure and CSF dynamics before and after carbonic anhydrase inhibition.

cerebrospinal fluid dynamics assessment

Direction: NEGATIVE

Trans-stenosis gradient and pressure coupling

pathophysiology#Venous sinus stenosis and intracranial venous hypertension

Measure the transverse-sinus trans-stenosis pressure gradient before and after intracranial pressure is lowered, and before and after stenting.

catheter cerebral venography pressure gradient measurement

Direction: POSITIVE

Decision criterion

A node is supported as initiating/upstream if its perturbation reproducibly and durably lowers intracranial pressure and normalizes the other axes.

Would support

pathophysiology#Metabolic risk background pathophysiology#Choroid plexus CSF hypersecretion pathophysiology#Venous sinus stenosis and intracranial venous hypertension

Show evidence (2 references)

PMID:33631966 SUPPORT Human Clinical

"Several mechanisms have been proposed as the underlying cause of IIH, such as an overproduction of cerebrospinal fluid (CSF), outflow obstruction, elevated pressure in the venous sinuses and more recently a dysfunction in the glymphatic pathway as well as hormonal alterations."

Directly enumerates the competing candidate mechanisms whose causal ordering is unresolved.

PMID:26700907 SUPPORT Human Clinical

"Pathogenesis has not been fully elucidated, but several causal factors have been proposed."

Confirms that the pathogenesis and causal ordering of the proposed factors remain unestablished.

⚙

Pathophysiology

8

Dysregulated cerebrospinal fluid dynamics

The central pathophysiologic problem in IIH is dysregulation of CSF dynamics, leading to persistently elevated intracranial pressure in the absence of a mass lesion.

choroid plexus epithelial cell CL:0000706

cerebrospinal fluid secretion GO:0033326 ⚠ ABNORMAL

Downstream

Elevated intracranial pressure CSF dysregulation produces sustained elevation of intracranial pressure.

Show evidence (1 reference)

PMID:34929642 SUPPORT Other

"The pathophysiology involves dysregulation of cerebrospinal fluid (CSF) dynamics and venous sinus pressure"

This directly supports dysregulated CSF dynamics as the core mechanism.

Elevated intracranial pressure

Persistently elevated intracranial pressure causes the characteristic neuro-ophthalmologic and headache syndrome of pseudotumor cerebri.

Downstream

Papilledema and visual injury Elevated pressure injures the optic nerve head and threatens vision.

Headache syndrome Elevated pressure produces the characteristic headache syndrome.

CGRP-mediated trigeminovascular headache signaling Raised pressure and altered intracranial compliance can engage trigeminovascular pain signaling, but mean pressure alone does not fully explain IIH headache.

Venous sinus stenosis and intracranial venous hypertension Raised intracranial pressure can compress the transverse sinuses, worsening venous sinus stenosis and closing a positive feedback loop.

Show evidence (1 reference)

PMID:38575259 SUPPORT Other

"Pseudotumor cerebri syndrome is a syndrome of increased cerebrospinal fluid pressure without ventriculomegaly, mass lesion, or meningeal abnormality."

This directly supports elevated CSF pressure as the defining proximal abnormality.

Metabolic risk background

IIH strongly favors obese women of reproductive age, and metabolic and hormonal factors are thought to amplify CSF and venous-pressure dysregulation.

Downstream

Dysregulated cerebrospinal fluid dynamics Metabolic and hormonal factors contribute to CSF and venous-pressure abnormalities.

Choroid plexus CSF hypersecretion Obesity-associated hormonal signalling acts on the choroid plexus epithelium to stimulate active CSF secretion.

Show evidence (1 reference)

PMID:34929642 SUPPORT Other

"IIH demonstrates a strong predilection towards obese women of reproductive age"

This supports the major metabolic-epidemiologic background on which IIH develops.

Choroid plexus CSF hypersecretion

Obesity-associated metabolic and hormonal signalling is proposed to act on the choroid plexus epithelium to drive active, Na+/K+-ATPase-dependent cerebrospinal fluid secretion, the secretory arm of dysregulated CSF dynamics. Two complementary hormonal pathways are implicated: adipose 11-beta-hydroxysteroid dehydrogenase type 1 activity, which regulates CSF secretion and tracks with intracranial pressure, and glucagon-like peptide-1 (GLP-1) receptor signalling on choroid plexus epithelium. Pharmacological proof-of-concept comes from 11-beta-HSD1 inhibition (AZD4017) and GLP-1 receptor agonism (exenatide) lowering intracranial pressure, although the 11-beta-HSD1 trial did not meet its primary endpoint.

Choroid Plexus CSF Hypersecretion (Metabolic-Hormonal) Model

choroid plexus epithelial cell CL:0000706

choroid plexus CSF hypersecretion GO:0033326 ↑ INCREASED

Downstream

Dysregulated cerebrospinal fluid dynamics Excess choroid plexus CSF secretion is the secretory component of dysregulated CSF dynamics.

Elevated intracranial pressure Increased CSF secretion raises CSF volume and contributes directly to sustained elevation of intracranial pressure.

Show evidence (3 references)

PMID:32954315 SUPPORT Human Clinical

"The enzyme 11β-hydroxysteroid dehydrogenase type 1 has been implicated in regulating cerebrospinal fluid secretion, and its activity is associated with alterations in intracranial pressure in idiopathic intracranial hypertension"

Supports 11β-HSD1-dependent regulation of choroid plexus CSF secretion as a driver of intracranial pressure, the mechanistic rationale for the AZD4017 trial.

PMID:36907221 SUPPORT Human Clinical

"Preclinical data have demonstrated a novel strategy to lower intracranial pressure using glucagon-like peptide-1 (GLP-1) receptor signalling"

Supports GLP-1 receptor signalling at the choroid plexus as a modifiable driver of CSF secretion and intracranial pressure.

PMID:36907221 SUPPORT Human Clinical

"Exenatide significantly and meaningfully lowered intracranial pressure at 2.5 h"

The exenatide randomized trial provides human proof-of-concept that modulating choroid plexus GLP-1 signalling lowers intracranial pressure.

Venous sinus stenosis and intracranial venous hypertension

Bilateral transverse and sigmoid sinus stenosis with a trans-stenosis pressure gradient raises intracranial venous pressure, impairing CSF absorption across the arachnoid granulations and contributing to raised intracranial pressure through a self-sustaining positive feedback loop. Whether venous sinus stenosis initiates the disease or is a pressure-dependent downstream consequence is debated, but relieving the gradient (for example by venous sinus stenting) can interrupt the loop.

dural venous sinus endothelium CL:0002543

Downstream

Dysregulated cerebrospinal fluid dynamics Elevated venous sinus pressure reduces the pressure gradient for CSF absorption across arachnoid granulations, worsening CSF dynamics.

Elevated intracranial pressure Intracranial venous hypertension contributes directly to sustained elevation of intracranial pressure.

Show evidence (3 references)

PMID:36114039 SUPPORT Other

"bilateral stenosis of the transverse sinuses that plays a major role in the pathogenesis of the disease by creating a positive feedback loop that increases intracranial venous hypertension and contributes to clinical manifestations"

Supports transverse sinus stenosis and a venous positive feedback loop as a core pathogenic mechanism of IIH.

PMID:34929642 SUPPORT Other

"The pathophysiology involves dysregulation of cerebrospinal fluid (CSF) dynamics and venous sinus pressure"

Supports elevated venous sinus pressure as a pathophysiologic axis co-equal with CSF dynamics.

PMID:28841117 SUPPORT Human Clinical

"Stenosis of the transverse sinus (TS) and sigmoid sinus (SS), with a trans-stenosis pressure gradient, has been implicated in the pathophysiology of idiopathic intracranial hypertension (IIH)."

Supports transverse/sigmoid sinus stenosis with a trans-stenosis pressure gradient as an implicated mechanism.

Papilledema and visual injury

Elevated intracranial pressure is transmitted to the subarachnoid space around the optic nerve, hindering axoplasmic transport in retinal ganglion cell axons and producing optic nerve head edema. Persistent papilledema can damage optic nerve fibers and threaten permanent visual loss if not recognized and treated.

retinal ganglion cell CL:0000740

optic nerve axonal transport GO:0098930 ↓ DECREASED

optic nerve UBERON:0000941

Show evidence (2 references)

PMID:34813854 SUPPORT Other

"Papilledema is caused by transmission of elevated ICP to the subarachnoid space surrounding the optic nerve that hinders axoplasmic transport within ganglion cell axons."

This review supports the pressure-transmission and axoplasmic-transport mechanism linking raised intracranial pressure to optic nerve head edema.

PMID:38575259 SUPPORT Other

"Permanent visual loss occurs if undetected or untreated"

This directly supports the optic-nerve/vision branch of the disease mechanism.

CGRP-mediated trigeminovascular headache signaling

IIH headache is frequently migraine-like and is partly mediated by trigeminovascular neuropeptide signaling rather than by mean intracranial pressure alone. CGRP provocation triggers typical IIH headache attacks and increases ICP pulse amplitude, supporting a pressure-compliance and neuropeptide signaling branch for headache morbidity.

trigeminal nociceptor CL:0000198

trigeminovascular pain signaling GO:0019233 ↑ INCREASED CGRP-mediated neuropeptide signaling GO:0007218 ⚠ ABNORMAL

dura mater UBERON:0002363 trigeminal ganglion UBERON:0001675

Downstream

Headache syndrome CGRP/neuropeptide activation of trigeminovascular pain pathways produces the migraine-like headache attacks that dominate IIH morbidity.

Show evidence (2 references)

PMID:41989095 SUPPORT Human Clinical

"CGRP reliably provoked typical IIH headache attacks (which have migraine-like features) and increased ICP pulse amplitude, as a measure of intracranial compliance, without altering mean pressure."

Randomized crossover provocation data support CGRP-dependent trigeminovascular signaling and altered pressure compliance as a mechanism for IIH headache attacks.

PMID:41989095 SUPPORT Human Clinical

"These findings provide mechanistic support for CGRP involvement in headache attributed to IIH and justify prospective evaluation of CGRP pathway blockade in this population."

The authors explicitly interpret the trial as mechanistic support for CGRP involvement in IIH-attributed headache.

Headache syndrome

Headache is the predominant symptomatic morbidity of pseudotumor cerebri. It reflects the elevated-pressure state, but current human provocation data support an additional CGRP-mediated trigeminovascular component that can vary independently of mean intracranial pressure.

Show evidence (1 reference)

PMID:35103000 SUPPORT Other

"headache is the predominant morbidity in over 90%."

This directly supports headache as the dominant symptomatic output of the pressure syndrome.

⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.

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Phenotypes

4

Ear 1

Pulsatile tinnitus Pulsatile tinnitus HP:0008629

Show evidence (1 reference)

PMID:34929642 SUPPORT Other

"The primary symptoms include headache, vision loss, and pulsatile tinnitus"

This directly supports pulsatile tinnitus as a primary symptom.

Eye 2

Papilledema Papilledema HP:0001085

Show evidence (1 reference)

PMID:34929642 SUPPORT Other

"Idiopathic intracranial hypertension (IIH) is characterized by increased intracranial pressure, manifested by papilledema"

This directly supports papilledema as a defining sign.

Visual loss FREQUENT Visual loss HP:0000572

Show evidence (2 references)

PMID:34929642 SUPPORT Other

"The primary symptoms include headache, vision loss, and pulsatile tinnitus"

This directly supports visual loss as a primary symptom.

clinicaltrials:NCT01003639 SUPPORT Human Clinical

"Because of pressure on the optic nerve (papilledema), 86% have some degree of permanent visual loss and 10% develop severe visual loss"

This quantitative trial summary supports visual loss as a frequent phenotype in pseudotumor cerebri.

Nervous System 1

Headache Headache HP:0002315

Show evidence (1 reference)

PMID:34929642 SUPPORT Other

"The primary symptoms include headache, vision loss, and pulsatile tinnitus"

This directly supports headache as a primary symptom.

💊

Medical Actions

2

Acetazolamide

Action: Pharmacotherapy NCIT:C15986

Agent: acetazolamide CHEBI:27690

Acetazolamide is the best-studied medical therapy and improves visual outcomes when combined with a weight-reduction program in patients with mild visual loss.

Target Phenotypes: Papilledema HP:0001085 Visual loss HP:0000572

Show evidence (1 reference)

PMID:24756514 SUPPORT Human Clinical

"In patients with IIH and mild visual loss, the use of acetazolamide with a low-sodium weight-reduction diet compared with diet alone resulted in modest improvement in visual field function."

This randomized trial directly supports acetazolamide as disease-relevant therapy.

Weight-reduction intervention

Action: dietary intervention MAXO:0000088

Weight reduction is a core disease-directed intervention in overweight patients with IIH.

Target Phenotypes: Headache HP:0002315 Papilledema HP:0001085

Show evidence (1 reference)

PMID:34929642 SUPPORT Other

"The Idiopathic Intracranial Hypertension Treatment Trial, the first of its kind randomized controlled trial on IIH, provides class I evidence for treatment with weight loss and acetazolamide."

This directly supports weight loss as a disease-directed intervention.

🔀

Differential Diagnoses

2

Conditions with similar clinical presentations that must be differentiated from pseudotumor cerebri:

Cerebral sinovenous thrombosis Not Yet Curated MONDO:0017993

Overlapping Features Venous sinus thrombosis can mimic IIH with papilledema and raised intracranial pressure and must be excluded on imaging.

Show evidence (1 reference)

PMID:39525793 SUPPORT Human Clinical

"Common causes of headaches during puerperium include pre-eclampsia, subarachnoid hemorrhage, cerebral venous thrombosis, meningitis, brain tumors, cerebrovascular diseases, and posterior reversible encephalopathy syndrome."

This directly identifies cerebral venous thrombosis as an important competing diagnosis in patients presenting with pseudotumor-cerebri-like headache and visual symptoms.

Brain neoplasm Not Yet Curated MONDO:0021211

Overlapping Features Intracranial mass lesions must be excluded before the diagnosis of pseudotumor cerebri is made.

Show evidence (1 reference)

PMID:12455560 SUPPORT Other

"The syndrome of increased intracranial pressure without hydrocephalus or mass lesion and with normal CSF composition, previously referred to as pseudotumor cerebri, is a diagnosis of exclusion now termed idiopathic intracranial hypertension (IIH)."

This directly supports exclusion of mass lesions such as brain neoplasms when diagnosing pseudotumor cerebri.

📊

Related Datasets

1

Effect of acetazolamide on visual function in patients with idiopathic intracranial hypertension and mild visual loss: the idiopathic intracranial hypertension treatment trial. PMID:24756514

Multicenter randomized controlled trial dataset capturing visual fields, papilledema grading, weight change, and headache-related outcomes in IIH.

Homo sapiens n=165

Conditions: idiopathic intracranial hypertension mild visual loss

PMID:24756514

Show evidence (1 reference)

PMID:24756514 SUPPORT Human Clinical

"Multicenter, randomized, double-masked, placebo-controlled study of acetazolamide in 165 participants with IIH and mild visual loss"

This supports the study as a reusable human interventional dataset for IIH.

🔬

Clinical Trials

1

NCT01003639 PHASE_III COMPLETED

Randomized placebo-controlled IIHTT trial testing acetazolamide plus low-sodium weight-reduction diet in patients with mild visual loss.

Target Phenotypes: Visual loss HP:0000572 Papilledema HP:0001085

Show evidence (1 reference)

clinicaltrials:NCT01003639 SUPPORT Human Clinical

"This trial will study subjects who have mild visual loss from IIH to (1) establish convincing, evidence-based treatment strategies for IIH to restore and protect vision, (2) follow subjects up to 4 years to observe the long-term treatment outcomes and (3) determine the cause of IIH."

The registered IIHTT trial directly targeted visual outcomes in IIH.

{ }

Source YAML

click to show

name: pseudotumor cerebri
creation_date: '2026-04-13T04:00:00Z'
updated_date: '2026-04-13T23:58:00Z'
description: >-
  Pseudotumor cerebri, now commonly framed as idiopathic intracranial
  hypertension (IIH) in its primary form, is a syndrome of elevated
  intracranial pressure without mass lesion, hydrocephalus, or abnormal CSF
  composition. The current mechanistic model emphasizes dysregulated CSF
  dynamics and elevated venous sinus pressure on a metabolic background strongly
  associated with obesity. Clinically, patients present with headache,
  papilledema, visual dysfunction, and pulsatile tinnitus, with risk of
  permanent visual loss if untreated.
category: Complex
parents:
- disease
- intracranial hypertension
disease_term:
  preferred_term: pseudotumor cerebri
  term:
    id: MONDO:0009468
    label: pseudotumor cerebri
synonyms:
- idiopathic intracranial hypertension
- IIH
pathophysiology:
- name: Dysregulated cerebrospinal fluid dynamics
  description: >-
    The central pathophysiologic problem in IIH is dysregulation of CSF
    dynamics, leading to persistently elevated intracranial pressure in the
    absence of a mass lesion.
  cell_types:
  - preferred_term: choroid plexus epithelial cell
    term:
      id: CL:0000706
      label: choroid plexus epithelial cell
  biological_processes:
  - preferred_term: cerebrospinal fluid secretion
    modifier: ABNORMAL
    term:
      id: GO:0033326
      label: cerebrospinal fluid secretion
  evidence:
  - reference: PMID:34929642
    reference_title: "Idiopathic intracranial hypertension: Pathophysiology, diagnosis and management."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      The pathophysiology involves dysregulation of cerebrospinal fluid (CSF) dynamics and venous sinus pressure
    explanation: This directly supports dysregulated CSF dynamics as the core mechanism.
  downstream:
  - target: Elevated intracranial pressure
    description: CSF dysregulation produces sustained elevation of intracranial pressure.
- name: Elevated intracranial pressure
  description: >-
    Persistently elevated intracranial pressure causes the characteristic
    neuro-ophthalmologic and headache syndrome of pseudotumor cerebri.
  evidence:
  - reference: PMID:38575259
    reference_title: The Pseudotumor Cerebri Syndrome.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Pseudotumor cerebri syndrome is a syndrome of increased cerebrospinal fluid pressure without ventriculomegaly, mass lesion, or meningeal abnormality.
    explanation: This directly supports elevated CSF pressure as the defining proximal abnormality.
  downstream:
  - target: Papilledema and visual injury
    description: Elevated pressure injures the optic nerve head and threatens vision.
  - target: Headache syndrome
    description: Elevated pressure produces the characteristic headache syndrome.
  - target: CGRP-mediated trigeminovascular headache signaling
    description: >-
      Raised pressure and altered intracranial compliance can engage
      trigeminovascular pain signaling, but mean pressure alone does not fully
      explain IIH headache.
  - target: Venous sinus stenosis and intracranial venous hypertension
    description: >-
      Raised intracranial pressure can compress the transverse sinuses, worsening
      venous sinus stenosis and closing a positive feedback loop.
    evidence:
    - reference: PMID:28841117
      reference_title: Transient resolution of venous sinus stenosis after high-volume lumbar puncture in a patient with idiopathic intracranial hypertension.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        This report suggests that TS and SS stenosis may be a downstream effect of elevated intracranial pressure in IIH, rather than its principal etiological mechanism.
      explanation: Supports a feedback edge in which raised intracranial pressure worsens venous sinus stenosis.
- name: Metabolic risk background
  description: >-
    IIH strongly favors obese women of reproductive age, and metabolic and
    hormonal factors are thought to amplify CSF and venous-pressure
    dysregulation.
  evidence:
  - reference: PMID:34929642
    reference_title: "Idiopathic intracranial hypertension: Pathophysiology, diagnosis and management."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      IIH demonstrates a strong predilection towards obese women of reproductive age
    explanation: This supports the major metabolic-epidemiologic background on which IIH develops.
  downstream:
  - target: Dysregulated cerebrospinal fluid dynamics
    description: Metabolic and hormonal factors contribute to CSF and venous-pressure abnormalities.
  - target: Choroid plexus CSF hypersecretion
    description: >-
      Obesity-associated hormonal signalling acts on the choroid plexus
      epithelium to stimulate active CSF secretion.
- name: Choroid plexus CSF hypersecretion
  description: >-
    Obesity-associated metabolic and hormonal signalling is proposed to act on
    the choroid plexus epithelium to drive active, Na+/K+-ATPase-dependent
    cerebrospinal fluid secretion, the secretory arm of dysregulated CSF
    dynamics. Two complementary hormonal pathways are implicated: adipose
    11-beta-hydroxysteroid dehydrogenase type 1 activity, which regulates CSF
    secretion and tracks with intracranial pressure, and glucagon-like
    peptide-1 (GLP-1) receptor signalling on choroid plexus epithelium.
    Pharmacological proof-of-concept comes from 11-beta-HSD1 inhibition
    (AZD4017) and GLP-1 receptor agonism (exenatide) lowering intracranial
    pressure, although the 11-beta-HSD1 trial did not meet its primary endpoint.
  cell_types:
  - preferred_term: choroid plexus epithelial cell
    term:
      id: CL:0000706
      label: choroid plexus epithelial cell
  biological_processes:
  - preferred_term: choroid plexus CSF hypersecretion
    modifier: INCREASED
    term:
      id: GO:0033326
      label: cerebrospinal fluid secretion
  evidence:
  - reference: PMID:32954315
    reference_title: "11β-Hydroxysteroid dehydrogenase type 1 inhibition in idiopathic intracranial hypertension: a double-blind randomized controlled trial."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The enzyme 11β-hydroxysteroid dehydrogenase type 1 has been implicated in regulating cerebrospinal fluid secretion, and its activity is associated with alterations in intracranial pressure in idiopathic intracranial hypertension
    explanation: >-
      Supports 11β-HSD1-dependent regulation of choroid plexus CSF secretion as a
      driver of intracranial pressure, the mechanistic rationale for the AZD4017
      trial.
  - reference: PMID:36907221
    reference_title: "The effect of GLP-1RA exenatide on idiopathic intracranial hypertension: a randomized clinical trial."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Preclinical data have demonstrated a novel strategy to lower intracranial pressure using glucagon-like peptide-1 (GLP-1) receptor signalling
    explanation: >-
      Supports GLP-1 receptor signalling at the choroid plexus as a modifiable
      driver of CSF secretion and intracranial pressure.
  - reference: PMID:36907221
    reference_title: "The effect of GLP-1RA exenatide on idiopathic intracranial hypertension: a randomized clinical trial."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Exenatide significantly and meaningfully lowered intracranial pressure at 2.5 h
    explanation: >-
      The exenatide randomized trial provides human proof-of-concept that
      modulating choroid plexus GLP-1 signalling lowers intracranial pressure.
  downstream:
  - target: Dysregulated cerebrospinal fluid dynamics
    description: >-
      Excess choroid plexus CSF secretion is the secretory component of
      dysregulated CSF dynamics.
    hypothesis_groups:
    - choroid_plexus_csf_hypersecretion
  - target: Elevated intracranial pressure
    description: >-
      Increased CSF secretion raises CSF volume and contributes directly to
      sustained elevation of intracranial pressure.
    hypothesis_groups:
    - choroid_plexus_csf_hypersecretion
- name: Venous sinus stenosis and intracranial venous hypertension
  description: >-
    Bilateral transverse and sigmoid sinus stenosis with a trans-stenosis
    pressure gradient raises intracranial venous pressure, impairing CSF
    absorption across the arachnoid granulations and contributing to raised
    intracranial pressure through a self-sustaining positive feedback loop.
    Whether venous sinus stenosis initiates the disease or is a
    pressure-dependent downstream consequence is debated, but relieving the
    gradient (for example by venous sinus stenting) can interrupt the loop.
  cell_types:
  - preferred_term: dural venous sinus endothelium
    term:
      id: CL:0002543
      label: vein endothelial cell
  evidence:
  - reference: PMID:36114039
    reference_title: "[Idiopathic intracranial hypertension: From physiopathological mechanisms to therapeutic decision]."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      bilateral stenosis of the transverse sinuses that plays a major role in the pathogenesis of the disease by creating a positive feedback loop that increases intracranial venous hypertension and contributes to clinical manifestations
    explanation: Supports transverse sinus stenosis and a venous positive feedback loop as a core pathogenic mechanism of IIH.
  - reference: PMID:34929642
    reference_title: "Idiopathic intracranial hypertension: Pathophysiology, diagnosis and management."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      The pathophysiology involves dysregulation of cerebrospinal fluid (CSF) dynamics and venous sinus pressure
    explanation: Supports elevated venous sinus pressure as a pathophysiologic axis co-equal with CSF dynamics.
  - reference: PMID:28841117
    reference_title: Transient resolution of venous sinus stenosis after high-volume lumbar puncture in a patient with idiopathic intracranial hypertension.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Stenosis of the transverse sinus (TS) and sigmoid sinus (SS), with a trans-stenosis pressure gradient, has been implicated in the pathophysiology of idiopathic intracranial hypertension (IIH).
    explanation: Supports transverse/sigmoid sinus stenosis with a trans-stenosis pressure gradient as an implicated mechanism.
  downstream:
  - target: Dysregulated cerebrospinal fluid dynamics
    description: >-
      Elevated venous sinus pressure reduces the pressure gradient for CSF
      absorption across arachnoid granulations, worsening CSF dynamics.
  - target: Elevated intracranial pressure
    description: >-
      Intracranial venous hypertension contributes directly to sustained
      elevation of intracranial pressure.
- name: Papilledema and visual injury
  description: >-
    Elevated intracranial pressure is transmitted to the subarachnoid space
    around the optic nerve, hindering axoplasmic transport in retinal ganglion
    cell axons and producing optic nerve head edema. Persistent papilledema can
    damage optic nerve fibers and threaten permanent visual loss if not
    recognized and treated.
  cell_types:
  - preferred_term: retinal ganglion cell
    term:
      id: CL:0000740
      label: retinal ganglion cell
  biological_processes:
  - preferred_term: optic nerve axonal transport
    modifier: DECREASED
    term:
      id: GO:0098930
      label: axonal transport
  locations:
  - preferred_term: optic nerve
    term:
      id: UBERON:0000941
      label: cranial nerve II
  evidence:
  - reference: PMID:34813854
    reference_title: "Papilledema: A review of etiology, pathophysiology, diagnosis, and management."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Papilledema is caused by transmission of elevated ICP to the subarachnoid space surrounding the optic nerve that hinders axoplasmic transport within ganglion cell axons.
    explanation: >-
      This review supports the pressure-transmission and axoplasmic-transport
      mechanism linking raised intracranial pressure to optic nerve head edema.
  - reference: PMID:38575259
    reference_title: The Pseudotumor Cerebri Syndrome.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Permanent visual loss occurs if undetected or untreated
    explanation: This directly supports the optic-nerve/vision branch of the disease mechanism.
- name: CGRP-mediated trigeminovascular headache signaling
  description: >-
    IIH headache is frequently migraine-like and is partly mediated by
    trigeminovascular neuropeptide signaling rather than by mean intracranial
    pressure alone. CGRP provocation triggers typical IIH headache attacks and
    increases ICP pulse amplitude, supporting a pressure-compliance and
    neuropeptide signaling branch for headache morbidity.
  cell_types:
  - preferred_term: trigeminal nociceptor
    term:
      id: CL:0000198
      label: pain receptor cell
  biological_processes:
  - preferred_term: trigeminovascular pain signaling
    modifier: INCREASED
    term:
      id: GO:0019233
      label: sensory perception of pain
  - preferred_term: CGRP-mediated neuropeptide signaling
    modifier: ABNORMAL
    term:
      id: GO:0007218
      label: neuropeptide signaling pathway
  locations:
  - preferred_term: dura mater
    term:
      id: UBERON:0002363
      label: dura mater
  - preferred_term: trigeminal ganglion
    term:
      id: UBERON:0001675
      label: trigeminal ganglion
  evidence:
  - reference: PMID:41989095
    reference_title: Calcitonin gene-related peptide induces headache attacks in people with idiopathic intracranial hypertension.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      CGRP reliably provoked typical IIH headache attacks (which have migraine-like features) and increased ICP pulse amplitude, as a measure of intracranial compliance, without altering mean pressure.
    explanation: >-
      Randomized crossover provocation data support CGRP-dependent
      trigeminovascular signaling and altered pressure compliance as a
      mechanism for IIH headache attacks.
  - reference: PMID:41989095
    reference_title: Calcitonin gene-related peptide induces headache attacks in people with idiopathic intracranial hypertension.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      These findings provide mechanistic support for CGRP involvement in headache attributed to IIH and justify prospective evaluation of CGRP pathway blockade in this population.
    explanation: >-
      The authors explicitly interpret the trial as mechanistic support for CGRP
      involvement in IIH-attributed headache.
  downstream:
  - target: Headache syndrome
    description: >-
      CGRP/neuropeptide activation of trigeminovascular pain pathways produces
      the migraine-like headache attacks that dominate IIH morbidity.
- name: Headache syndrome
  description: >-
    Headache is the predominant symptomatic morbidity of pseudotumor cerebri.
    It reflects the elevated-pressure state, but current human provocation data
    support an additional CGRP-mediated trigeminovascular component that can
    vary independently of mean intracranial pressure.
  evidence:
  - reference: PMID:35103000
    reference_title: Idiopathic Intracranial Hypertension - Challenges and Pearls.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      headache is the predominant morbidity in over 90%.
    explanation: This directly supports headache as the dominant symptomatic output of the pressure syndrome.
phenotypes:
- name: Headache
  category: Neurologic
  description: >-
    Headache is the dominant symptomatic burden in pseudotumor cerebri.
  phenotype_term:
    preferred_term: Headache
    term:
      id: HP:0002315
      label: Headache
  evidence:
  - reference: PMID:34929642
    reference_title: "Idiopathic intracranial hypertension: Pathophysiology, diagnosis and management."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      The primary symptoms include headache, vision loss, and pulsatile tinnitus
    explanation: This directly supports headache as a primary symptom.
- name: Papilledema
  category: Ophthalmic
  diagnostic: true
  description: >-
    Papilledema is the hallmark neuro-ophthalmologic sign of raised
    intracranial pressure in IIH.
  phenotype_term:
    preferred_term: Papilledema
    term:
      id: HP:0001085
      label: Papilledema
  evidence:
  - reference: PMID:34929642
    reference_title: "Idiopathic intracranial hypertension: Pathophysiology, diagnosis and management."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Idiopathic intracranial hypertension (IIH) is characterized by increased intracranial pressure, manifested by papilledema
    explanation: This directly supports papilledema as a defining sign.
- name: Visual loss
  category: Ophthalmic
  frequency: FREQUENT
  description: >-
    Visual dysfunction and permanent visual loss can occur if elevated
    intracranial pressure is not controlled.
  phenotype_term:
    preferred_term: Visual loss
    term:
      id: HP:0000572
      label: Visual loss
  evidence:
  - reference: PMID:34929642
    reference_title: "Idiopathic intracranial hypertension: Pathophysiology, diagnosis and management."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      The primary symptoms include headache, vision loss, and pulsatile tinnitus
    explanation: This directly supports visual loss as a primary symptom.
  - reference: clinicaltrials:NCT01003639
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Because of pressure on the optic nerve (papilledema), 86% have some degree of permanent visual loss and 10% develop severe visual loss
    explanation: This quantitative trial summary supports visual loss as a frequent phenotype in pseudotumor cerebri.
- name: Pulsatile tinnitus
  category: Otolaryngologic
  description: >-
    Pulsatile tinnitus is a common pressure-related symptom in pseudotumor
    cerebri.
  phenotype_term:
    preferred_term: Pulsatile tinnitus
    term:
      id: HP:0008629
      label: Pulsatile tinnitus
  evidence:
  - reference: PMID:34929642
    reference_title: "Idiopathic intracranial hypertension: Pathophysiology, diagnosis and management."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      The primary symptoms include headache, vision loss, and pulsatile tinnitus
    explanation: This directly supports pulsatile tinnitus as a primary symptom.
treatments:
- name: Acetazolamide
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: acetazolamide
      term:
        id: CHEBI:27690
        label: acetazolamide
  description: >-
    Acetazolamide is the best-studied medical therapy and improves visual
    outcomes when combined with a weight-reduction program in patients with mild
    visual loss.
  target_phenotypes:
  - preferred_term: Papilledema
    term:
      id: HP:0001085
      label: Papilledema
  - preferred_term: Visual loss
    term:
      id: HP:0000572
      label: Visual loss
  evidence:
  - reference: PMID:24756514
    reference_title: "Effect of acetazolamide on visual function in patients with idiopathic intracranial hypertension and mild visual loss: the idiopathic intracranial hypertension treatment trial."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In patients with IIH and mild visual loss, the use of acetazolamide with a low-sodium weight-reduction diet compared with diet alone resulted in modest improvement in visual field function.
    explanation: This randomized trial directly supports acetazolamide as disease-relevant therapy.
- name: Weight-reduction intervention
  treatment_term:
    preferred_term: dietary intervention
    term:
      id: MAXO:0000088
      label: dietary intervention
  description: >-
    Weight reduction is a core disease-directed intervention in overweight
    patients with IIH.
  target_phenotypes:
  - preferred_term: Headache
    term:
      id: HP:0002315
      label: Headache
  - preferred_term: Papilledema
    term:
      id: HP:0001085
      label: Papilledema
  evidence:
  - reference: PMID:34929642
    reference_title: "Idiopathic intracranial hypertension: Pathophysiology, diagnosis and management."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      The Idiopathic Intracranial Hypertension Treatment Trial, the first of its kind randomized controlled trial on IIH, provides class I evidence for treatment with weight loss and acetazolamide.
    explanation: This directly supports weight loss as a disease-directed intervention.
diagnosis:
- name: Magnetic resonance imaging
  diagnosis_term:
    preferred_term: magnetic resonance imaging procedure
    term:
      id: MAXO:0000424
      label: magnetic resonance imaging procedure
  description: >-
    Neuroimaging is required to exclude mass lesion and other structural causes
    of intracranial hypertension.
  results: Normal brain imaging without mass lesion supports IIH after exclusion of secondary causes.
  evidence:
  - reference: PMID:12455560
    reference_title: Diagnostic criteria for idiopathic intracranial hypertension.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Since then, new developments, including advances in neuroimaging technology and recognition of additional secondary causes of intracranial hypertension, have further enhanced the ability to diagnose conditions that may mimic IIH.
    explanation: This supports neuroimaging as a required diagnostic step.
- name: Lumbar puncture with opening pressure measurement
  description: >-
    Diagnostic lumbar puncture is used to document elevated opening pressure and
    normal CSF composition.
  results: Elevated opening pressure with normal CSF composition supports the diagnosis.
  evidence:
  - reference: PMID:12455560
    reference_title: Diagnostic criteria for idiopathic intracranial hypertension.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      The syndrome of increased intracranial pressure without hydrocephalus or mass lesion and with normal CSF composition
    explanation: This directly supports lumbar puncture-based confirmation of pressure elevation with normal CSF composition.
differential_diagnoses:
- name: Cerebral sinovenous thrombosis
  disease_term:
    preferred_term: cerebral sinovenous thrombosis
    term:
      id: MONDO:0017993
      label: cerebral sinovenous thrombosis
  description: >-
    Venous sinus thrombosis can mimic IIH with papilledema and raised
    intracranial pressure and must be excluded on imaging.
  evidence:
  - reference: PMID:39525793
    reference_title: "Idiopathic intracranial hypertension following childbirth: a case report and management strategies."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Common causes of headaches during puerperium include pre-eclampsia, subarachnoid hemorrhage, cerebral venous thrombosis, meningitis, brain tumors, cerebrovascular diseases, and posterior reversible encephalopathy syndrome.
    explanation: This directly identifies cerebral venous thrombosis as an important competing diagnosis in patients presenting with pseudotumor-cerebri-like headache and visual symptoms.
- name: Brain neoplasm
  disease_term:
    preferred_term: brain neoplasm
    term:
      id: MONDO:0021211
      label: brain neoplasm
  description: >-
    Intracranial mass lesions must be excluded before the diagnosis of
    pseudotumor cerebri is made.
  evidence:
  - reference: PMID:12455560
    reference_title: Diagnostic criteria for idiopathic intracranial hypertension.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      The syndrome of increased intracranial pressure without hydrocephalus or mass lesion and with normal CSF composition, previously referred to as pseudotumor cerebri, is a diagnosis of exclusion now termed idiopathic intracranial hypertension (IIH).
    explanation: This directly supports exclusion of mass lesions such as brain neoplasms when diagnosing pseudotumor cerebri.
clinical_trials:
- name: NCT01003639
  phase: PHASE_III
  status: COMPLETED
  description: >-
    Randomized placebo-controlled IIHTT trial testing acetazolamide plus
    low-sodium weight-reduction diet in patients with mild visual loss.
  target_phenotypes:
  - preferred_term: Visual loss
    term:
      id: HP:0000572
      label: Visual loss
  - preferred_term: Papilledema
    term:
      id: HP:0001085
      label: Papilledema
  evidence:
  - reference: clinicaltrials:NCT01003639
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      This trial will study subjects who have mild visual loss from IIH to (1) establish convincing, evidence-based treatment strategies for IIH to restore and protect vision, (2) follow subjects up to 4 years to observe the long-term treatment outcomes and (3) determine the cause of IIH.
    explanation: The registered IIHTT trial directly targeted visual outcomes in IIH.
datasets:
- accession: PMID:24756514
  title: "Effect of acetazolamide on visual function in patients with idiopathic intracranial hypertension and mild visual loss: the idiopathic intracranial hypertension treatment trial."
  description: >-
    Multicenter randomized controlled trial dataset capturing visual fields,
    papilledema grading, weight change, and headache-related outcomes in IIH.
  organism:
    preferred_term: Homo sapiens
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  sample_count: 165
  conditions:
  - idiopathic intracranial hypertension
  - mild visual loss
  publication: PMID:24756514
  evidence:
  - reference: PMID:24756514
    reference_title: "Effect of acetazolamide on visual function in patients with idiopathic intracranial hypertension and mild visual loss: the idiopathic intracranial hypertension treatment trial."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Multicenter, randomized, double-masked, placebo-controlled study of acetazolamide in 165 participants with IIH and mild visual loss
    explanation: This supports the study as a reusable human interventional dataset for IIH.
mechanistic_hypotheses:
- hypothesis_group_id: choroid_plexus_csf_hypersecretion
  hypothesis_label: Choroid Plexus CSF Hypersecretion (Metabolic-Hormonal) Model
  status: EMERGING
  description: >-
    A converging working model places obesity-associated metabolic and hormonal
    dysregulation upstream of choroid plexus cerebrospinal fluid hypersecretion as
    the primary driver of raised intracranial pressure. Visceral adiposity is
    proposed to elevate adipose 11-beta-hydroxysteroid dehydrogenase type 1
    activity and circulating androgens, and obesity-associated GLP-1 signaling is
    proposed to act on choroid plexus epithelium, together stimulating choroid
    plexus Na+/K+-ATPase-driven CSF secretion. Pharmacological proof-of-concept
    from 11-beta-HSD1 inhibition and GLP-1 receptor agonism reducing intracranial
    pressure has driven interest in this model, and on this view transverse sinus
    stenosis is an amplifying feedback consequence of raised pressure rather than
    the initiating lesion.
  evidence:
  - reference: PMID:34929642
    reference_title: "Idiopathic intracranial hypertension: Pathophysiology, diagnosis and management."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      recent studies highlighting the pathogenic role of metabolic and hormonal factors have led to the identification of several pharmacological targets and development of novel therapeutic agents
    explanation: >-
      This supports a metabolic-hormonal driver upstream of CSF dynamics and the
      emergence of targeted pharmacological therapies consistent with the
      choroid plexus hypersecretion model.
  notes: >-
    Status EMERGING rather than CANONICAL because the human evidence linking
    specific hormonal axes to choroid plexus secretion is still maturing. A
    dedicated Choroid plexus CSF hypersecretion pathophysiology node now
    represents the secretory arm anchored on the AZD4017 (11-beta-HSD1) and
    exenatide (GLP-1) randomized trials, but the 11-beta-HSD1 trial did not meet
    its primary endpoint, so the upstream hormonal mechanism remains a working
    model rather than established causation.
- hypothesis_group_id: primary_venous_sinus_obstruction
  hypothesis_label: Primary Venous Sinus Obstruction Model
  status: ALTERNATIVE
  description: >-
    An alternative model proposes transverse/sigmoid venous sinus stenosis as the
    initiating lesion: elevated dural venous sinus pressure impairs CSF absorption
    at the arachnoid granulations and raises intracranial pressure. The
    cause-versus-consequence relationship between sinus stenosis and raised
    pressure is not fully resolved, since stenosis frequently reverses after
    pressure is lowered; many authors now regard it as an amplifying feedback loop
    rather than the primary cause, though venous sinus stenting benefits a subset
    of patients.
  evidence:
  - reference: PMID:34929642
    reference_title: "Idiopathic intracranial hypertension: Pathophysiology, diagnosis and management."
    supports: PARTIAL
    evidence_source: OTHER
    snippet: >-
      The pathophysiology involves dysregulation of cerebrospinal fluid (CSF) dynamics and venous sinus pressure
    explanation: >-
      Venous sinus pressure is recognized as part of IIH pathophysiology, but the
      review frames it alongside CSF dynamics rather than as the established
      primary cause, consistent with an alternative/contributory rather than
      canonical role.
discussions:
- discussion_id: gap_iih_headache_mechanism
  prompt: >-
    What is the proximate mechanism of headache in IIH, and why is it imperfectly
    coupled to the degree of intracranial pressure elevation?
  kind: KNOWLEDGE_GAP
  status: OPEN
  attaches_to:
  - pathophysiology#Headache syndrome
  - pathophysiology#CGRP-mediated trigeminovascular headache signaling
  rationale: >-
    Headache is the dominant symptomatic morbidity but its mechanism is only
    partly understood. Human CGRP provocation data now support
    trigeminovascular neuropeptide signaling and ICP pulsatility as a proximal
    mechanism, while headache can still persist or fluctuate independently of
    measured pressure. Modeling headache purely as a downstream consequence of
    raised mean pressure remains incomplete.
- discussion_id: gap_iih_venous_stenosis_cause_or_consequence
  prompt: >-
    Is transverse venous sinus stenosis a primary initiating lesion or a
    pressure-dependent feedback consequence in IIH?
  kind: KNOWLEDGE_GAP
  status: OPEN
  attaches_to:
  - pathophysiology#Venous sinus stenosis and intracranial venous hypertension
  - pathophysiology#Dysregulated cerebrospinal fluid dynamics
  - pathophysiology#Elevated intracranial pressure
  rationale: >-
    Transverse sinus stenosis is present in most patients and venous sinus
    stenting helps a subset, yet stenosis can reverse once intracranial pressure
    is lowered. Whether it initiates the disease or amplifies an
    already-elevated-pressure state is unresolved and distinguishes the primary
    venous obstruction model from the choroid plexus hypersecretion model.
- discussion_id: gap_iih_sex_and_nonobese_predilection
  prompt: >-
    Why does IIH predominantly affect obese women of reproductive age, and what
    distinguishes the mechanism in non-obese or atypical cases?
  kind: KNOWLEDGE_GAP
  status: OPEN
  attaches_to:
  - pathophysiology#Metabolic risk background
  - pathophysiology#Choroid plexus CSF hypersecretion
  rationale: >-
    The strong predilection for obese women of reproductive age implicates sex
    hormone modulation of choroid plexus secretory capacity, but the responsible
    axis is not fully characterized. A minority of patients are non-obese,
    suggesting a distinct or additional primary mechanism (e.g., medication
    exposure or venous anomaly) that the current metabolic-background node does
    not yet capture.
- discussion_id: gap_iih_obesity_venous_csf_hierarchy
  prompt: >-
    How do obesity/metabolic-hormonal drivers, venous sinus pressure and
    stenosis, and CSF production/absorption interact causally in IIH, and which
    of these is the initiating event versus an amplifying feedback consequence?
  kind: KNOWLEDGE_GAP
  status: OPEN
  attaches_to:
  - pathophysiology#Metabolic risk background
  - pathophysiology#Choroid plexus CSF hypersecretion
  - pathophysiology#Venous sinus stenosis and intracranial venous hypertension
  - pathophysiology#Dysregulated cerebrospinal fluid dynamics
  rationale: >-
    IIH is defined by raised intracranial pressure without a mass lesion, yet the
    causal ordering among its candidate mechanisms remains unresolved. Multiple
    pathways have been proposed as the underlying cause - choroid plexus CSF
    overproduction, impaired CSF outflow/absorption, elevated venous sinus
    pressure with transverse sinus stenosis, glymphatic dysfunction, and
    obesity-associated hormonal alterations - but no single theory explains the
    entire clinical picture. The metabolic-hormonal arm is an
    attractive upstream driver because pharmacological modulation lowers
    intracranial pressure, yet the AZD4017 trial missed its primary endpoint and
    the human evidence linking specific hormonal axes to choroid plexus secretion
    is still maturing. Venous sinus stenosis is present in most patients and
    stenting helps a subset, but stenosis frequently reverses once pressure is
    lowered, so it may amplify rather than initiate the disease via a positive
    feedback loop. There is even emerging argument that CSF overproduction is
    unlikely to be the primary driver and that carbonic-anhydrase inhibition
    targets a consequence rather than the cause. Disentangling which node is
    initiating versus secondary across obese, non-obese, and atypical patients is
    the central unresolved question and would reorder the entire pathophysiology
    DAG and its therapeutic targets.
  proposed_experiments:
  - experiment_id: exp_iih_mechanism_perturbation_ordering
    name: Interventional perturbation cohort to order metabolic, venous, and CSF mechanisms
    description: >-
      Enroll newly diagnosed IIH patients (obese and non-obese strata) and apply
      mechanism-specific perturbations with simultaneous multi-axis monitoring.
    experiment_type:
      preferred_term: prospective interventional mechanistic cohort study
    readouts:
    - name: Metabolic-hormonal response and intracranial pressure
      target: pathophysiology#Metabolic risk background
      description: >
        Quantify circulating metabolic and hormonal markers and body composition
        alongside intracranial pressure during a metabolic-hormonal intervention.
      assays:
      - preferred_term: serum hormone quantification
      - preferred_term: lumbar puncture opening pressure measurement
      direction: NEGATIVE
    - name: CSF secretion response to carbonic anhydrase inhibition
      target: pathophysiology#Choroid plexus CSF hypersecretion
      description: >
        Measure intracranial pressure and CSF dynamics before and after carbonic
        anhydrase inhibition.
      assays:
      - preferred_term: cerebrospinal fluid dynamics assessment
      direction: NEGATIVE
    - name: Trans-stenosis gradient and pressure coupling
      target: pathophysiology#Venous sinus stenosis and intracranial venous hypertension
      description: >
        Measure the transverse-sinus trans-stenosis pressure gradient before and
        after intracranial pressure is lowered, and before and after stenting.
      assays:
      - preferred_term: catheter cerebral venography pressure gradient measurement
      direction: POSITIVE
    decision_criterion: >-
      A node is supported as initiating/upstream if its perturbation reproducibly
      and durably lowers intracranial pressure and normalizes the other axes.
    would_support:
    - pathophysiology#Metabolic risk background
    - pathophysiology#Choroid plexus CSF hypersecretion
    - pathophysiology#Venous sinus stenosis and intracranial venous hypertension
  evidence:
  - reference: PMID:33631966
    reference_title: Diagnosis and treatment of idiopathic intracranial hypertension.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Several mechanisms have been proposed
      as the underlying cause of IIH, such as an overproduction of cerebrospinal fluid
      (CSF), outflow obstruction, elevated pressure in the venous sinuses and more
      recently a dysfunction in the glymphatic pathway as well as hormonal alterations.
    explanation: >-
      Directly enumerates the competing candidate mechanisms whose causal
      ordering is unresolved.
  - reference: PMID:26700907
    reference_title: "Understanding idiopathic intracranial hypertension: mechanisms, management, and future directions."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Pathogenesis has not been fully elucidated, but several causal factors have been
      proposed.
    explanation: >-
      Confirms that the pathogenesis and causal ordering of the proposed factors
      remain unestablished.

📚

References & Deep Research

Deep Research

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Asta Literature Retrieval: Pathophysiology and clinical mechanisms of pseudotumor cerebri. Core disease mechanisms, molecular and cellular pathw...

Asta Scientific Corpus Retrieval 20 citations 2026-04-13T13:54:04.205511

Asta Literature Retrieval: Pathophysiology and clinical mechanisms of pseudotumor cerebri. Core disease mechanisms, molecular and cellular pathw...

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Papers retrieved: 20
Snippets retrieved: 20

Relevant Papers

[1] Changes in Serum Proteomic Profiles at Different Stages of Pregnancy Toxemia in Goats

Authors: M. Uzti̇mür, C. N. Ünal, Gurler Akpinar
Year: 2025
Venue: Journal of Veterinary Internal Medicine
URL: https://www.semanticscholar.org/paper/4b9c488b5dbd65d7b26fd2ad9aed70e8c4b59942
DOI: 10.1111/jvim.70139
PMID: 40492724
PMCID: 12150350
Summary: Understanding the serum proteome profiles of goats with pregnancy toxemia might help identify the proteomes and pathways responsible for the development of this disease and improve diagnosis and treatment.
Evidence snippets:
Snippet 1 (score: 0.364) > The pathophysiology and progression of this disease are not fully understood. > Traditional biomedical research has focused on the analysis of single genes, proteins, metabolites, or metabolic pathways in diseases. This molecular reductionist approach is based on the assumption that identifying genetic variations and molecular components will lead to new treatments for diseases [13][14][15][16]. However, many diseases are complex and multifactorial, and in order to determine the phenotype of such diseases, it is necessary to understand the changes that occur in more than one gene, pathway, protein, or metabolite at the cellular, tissue, and organismal levels [17][18][19]. Therefore, in recent years, proteomics, as one field of multi-omics technologies, has helped in evaluating the complex pathogenetic mechanisms of different diseases from a broad perspective and has made substantial contributions [20,21]. In veterinary medicine, proteomic analysis of metabolic diseases such as ketosis [16], hypocalcemia [22], and fatty liver [23] in dairy cows has contributed valuable insights for the definition of new pathophysiological pathways and new diagnosis and treatment protocols for these diseases. The proteomic approach can contribute importantly to a broad and detailed understanding of the changes that occur at the organismal level associated with the increase in BHBA concentration in goats with pregnancy toxemia. Our aim was to evaluate the serum protein profiles of goats with SPT or CPT using proteomic techniques to determine the proteomic profiles of these animals and to identify the relevant pathophysiological mechanisms.

[2] Molecular Mechanisms and Risk Factors for the Pathogenesis of Hydrocephalus

Authors: Jing-wen Li, Xinjie Zhang, Jianfeng Guo, Chen Yu, Jun Yang
Year: 2022
Venue: Frontiers in Genetics
URL: https://www.semanticscholar.org/paper/d53bdf5f73f54a6d5a8be8777d23c465a13e9185
DOI: 10.3389/fgene.2021.777926
PMID: 35047005
PMCID: 8762052
Citations: 15
Influential citations: 2
Summary: Some possible fundamental molecular mechanisms and facilitating risk factors involved in the pathogenesis of hydrocephalus are elicited, and knowledge could be used to improve patient care in different ways, such as early precise diagnosis and effective therapeutic regimens.
Evidence snippets:
Snippet 1 (score: 0.361) > Cwh43 modifies the glycosylphosphatidylinositol-anchored proteins on the ependymal cells, and the mutant Cwh43 is related to iNPH in both humans and mice. The clinical features manifest as late-onset communicating hydrocephalus with symptoms of gait and balance dysfunction (Yang et al., 2021a). > The clinical manifestation and progression, as well as experimental investigations, indicate that hydrocephalus is a complex disease with polygenic involvement, rather than a simple CSF accumulation disorder. Although the current studies have revealed that some genetic mutations are involved in the pathogenesis of hydrocephalus, how these mutations are associated with the disorder of CSF circulation and their pathogenic roles in the pathological progression of hydrocephalus still remain largely unknown. Previous studies indicated that a lot of genetic mutations were relevant to the disorders of ciliary and/or centrosome, resulting in the dysfunction of the glymphatic system. However, how these mutations and their interactions contribute to the pathogenesis of hydrocephalus needs to be further elucidated. Moreover, there is still a lack of basic knowledge on the mechanisms underlying the cognitive functional impairment of hydrocephalus. Therefore, further extensive studies should be conducted to explore the underlying molecular mechanisms of identified and/or unidentified genes in the pathophysiology of hydrocephalus. Based on our knowledge, we propose that the genetic mutations relevant to ciliary and centrosomal proteins and the interaction between glymphatic system and ciliary/ centrosomal structures/functions may be a critical molecular mechanism in the pathophysiology of hydrocephalus. In addition, based on these fundamental molecular mechanisms, it is noteworthy that environmental and other acquired risks or etiological factors are also involved in the facilitation of ventricular enlargement.

[3] Molecular and cellular characteristics of cerebrovascular cell types and their contribution to neurodegenerative diseases

Authors: F. J. García, Myriam Heiman
Year: 2025
Venue: Molecular Neurodegeneration
URL: https://www.semanticscholar.org/paper/651ecb2269ae562236345f2451cab13e3d495216
DOI: 10.1186/s13024-025-00799-z
PMID: 39881338
PMCID: 11780804
Citations: 6
Summary: The current understanding of cerebrovasculature structure, function, and cell type diversity and its role in the mechanisms underlying various neurodegenerative diseases is described.
Evidence snippets:
Snippet 1 (score: 0.356) > Aging-associated neurodegenerative diseases exhibit distinct patterns of enhanced vulnerability, whereby specific populations of neurons are earliest and most affected in each disease [1]. Disease symptoms and progression, in turn, reflect the dysfunction of these most vulnerable cell types and associated circuits. In many cases, it is not into the molecular basis underlying cell structure and function [4][5][6][7]. Furthermore, single cell studies of specific neurodegenerative diseases have focused on profiling cells in the affected brain regions to understand cell type-specific dysregulation with the potential of uncovering disease-relevant gene expression patterns that could lead into the development of novel therapeutic strategies [8][9][10][11][12]. These studies have highlighted the interplay between affected neurons and other cell types of the brain, especially with identification of disease-associated genes that are enriched in non-neuronal cell populations, such as microglia and cerebrovascular cell types [13,14]. > In recent years, the cerebrovasculature and its role in the pathophysiology of neurodegenerative diseases has become a topic of considerable research focus. Despite extensive clinical data documenting functional changes in cerebrovascular function, especially at early stages of disease, the precise cellular and molecular mechanisms underlying these changes, particularly in humans, are not fully understood. Common themes of cerebrovasculature dysfunction, such as aberrant angiogenesis, decreases in tight junction expression, and increased transcytosis, have been noted, but the exact contributions of specific cerebrovascular cell types, and more importantly, their causal contribution to disease mechanisms are unknown. However, with the advent of a single cell atlas of the mouse cerebrovasculature, a framework for studying the molecular profiles of cerebrovascular cell types has been recently established [15]. This work provided a reference for several subsequent human atlases and the corresponding molecular changes within these cell types that occur across development and disease [14,[16][17][18][19][20]. > This review focuses on our current understanding of cerebrovasculature structure and function and its role in neurodegenerative diseases.

[4] Organoids in gastrointestinal diseases: from bench to clinic

Authors: Qinying Wang, Fanying Guo, Qinyuan Zhang, Tingting Hu, Yutao Jin et al.
Year: 2024
Venue: MedComm
URL: https://www.semanticscholar.org/paper/9b8880d8b9d45670da950197d7e353794f51d09e
DOI: 10.1002/mco2.574
PMID: 38948115
PMCID: 11214594
Citations: 12
Summary: A comprehensive and systematical depiction of organoids models is drawn, providing a novel insight into the utilization of organoids models from bench to clinic and clinical adhibition.
Evidence snippets:
Snippet 1 (score: 0.354) > Organoids models offer a robust platform for investigating the potential mechanisms of GI diseases and evaluating potential therapeutic interventions.By culturing organoids derived from patients' tissues or stem cells, researchers can delve into disease-specific cellular and molecular pathways, encompassing aberrant cell signaling, perturbed immune responses, and dysfunctional metabolic processes.These disease-specific phenotypes enable the study of disease progression, screening of prospective therapeutics, as well as identification of novel drug targets and mechanisms of action for GI diseases in a clinically relevant context.

[5] Recent advances in modelling of cerebellar ataxia using induced pluripotent stem cells

Authors: M. M. Wong, L. Watson, Esther B. E. Becker
Year: 2017
Venue: Journal of neurology & neuromedicine
URL: https://www.semanticscholar.org/paper/0d962652305116e383ab260b9e82d3a5ffe1722f
DOI: 10.29245/2572.942X/2017/7.1134
PMID: 28825058
PMCID: 5558869
Citations: 9
Summary: This review focuses on recent breakthroughs in generating human iPSC-derived Purkinje cells and highlights the future challenges that will need to be addressed in order to fully exploit these models for the modelling of the molecular mechanisms underlying cerebellar ataxias and the development of effective therapeutics.
Evidence snippets:
Snippet 1 (score: 0.353) > dominant polyglutamine spinocerebellar ataxias (SCAs) are the most studied forms of ataxias. Despite significant clinical and genetic heterogeneity, emerging evidence points to the existence of common pathogenic mechanisms that may be shared by several genetically distinct forms of cerebellar ataxias (reviewed in5-8). However, it is still unclear how the proposed pathological pathways ultimately result in cerebellar dysfunction and degeneration, predominantly affecting Purkinje cells. > Understanding disease mechanisms is key to treating neurodegenerative disorders. The heterogeneous nature of the cerebellar ataxias combined with the unavailability of human brain tissue and the lack of reliable disease models have, however, hampered our understanding of the molecular disease mechanisms underlying cerebellar ataxias and thus, the development of effective therapies. Although mouse models of several cerebellar ataxias, including FRDA and SCAs, have provided valuable insights into the pathophysiology of these disorders (reviewed in9), many questions remain about the observed species differences in disease phenotypes and the effectiveness of potential drugs in clinical trials. > To help translate research from animal models into novel treatments for ataxia patients, it is essential to validate findings in the relevant affected human cell types, particularly in cerebellar Purkinje cells. The current obstacles might be overcome by exploiting recently developed human induced pluripotent stem cell (iPSC) technology and neuronal differentiation protocols.

[6] New therapeutic targets in rare genetic skeletal diseases

Authors: M. Briggs, Peter A. Bell, M. Wright, K. A. Pirog
Year: 2015
Venue: Expert Opinion on Orphan Drugs
URL: https://www.semanticscholar.org/paper/1363107f71ae6d2d60abca471cddf3da5d13644b
DOI: 10.1517/21678707.2015.1083853
PMID: 26635999
PMCID: 4643203
Citations: 37
Influential citations: 1
Summary: An overview of disease mechanisms that are shared amongst groups of different GSDs and potential therapeutic approaches that are under investigation are described to generate critical mass for the identification and validation of novel therapeutic targets and biomarkers.
Evidence snippets:
Snippet 1 (score: 0.352) > proteins of the cartilage ECM such as type II collagen [50]. However, emerging knowledge suggests that the primary genetic defect may be less important than the cells' response to the expression of the mutant gene product [107]. Moreover, the largely overlooked response of a cell (i.e. chondrocyte) to the abnormal extracellular environment is also important for disease progression as illustrated by several GSDs discussed in this review. > It is important that 'omics'-based approaches and technologies are systematically applied to the study of rare GSDs so that definitive reference profiles and disease signatures are generated for each phenotype. These can then be used in a Systems Biology approach to identify both common and dissimilar pathological signatures and disease mechanisms. This approach is entirely dependent upon relevant in vitro and in vivo models (and also novel 'disease-mechanism phenocopies' [107]) for testing new diagnostic and prognostic tools and for determining the molecular mechanisms that underpin the pathophysiology so that effective therapeutic treatments can be developed and validated. This approach will eventually lead to personalized treatments and care strategies centred on shared disease mechanisms with the use of relevant biomarkers to monitor the efficacy of treatment and disease progression. > It is vital that all relevant stakeholders are involved from the outset in defining the appropriate outcomes of any potential therapeutic regime. The perceptions of a successful therapy can differ widely between the clinical academic community and the relevant patient-support groups and it is vital that there is engagement on all these issues. > In summary, the identification of causative genes and mutations for GSDs over the last 20 years, coupled with the generation and in-depth analysis of a plethora of relevant cell and mouse models, has derived new knowledge on disease mechanisms and suggested potential therapeutic targets. The fast-evolving hypothesis that clinically disparate diseases can share common disease mechanisms is a powerful concept that will generate critical mass for the identification and validation of novel therapeutic targets and biomarkers.

[7] Nasopharyngeal Carcinoma Signaling Pathway: An Update on Molecular Biomarkers

Authors: W. Tulalamba, T. Janvilisri
Year: 2012
Venue: International Journal of Cell Biology
URL: https://www.semanticscholar.org/paper/307cb9186444d9dad6e2e3b53763be0de76de186
DOI: 10.1155/2012/594681
PMID: 22500174
PMCID: 3303613
Citations: 93
Influential citations: 5
Summary: The molecular signaling pathways in the NPC are discussed for the holistic view of NPC development and progression and the important insights toward NPC pathogenesis may offer strategies for identification of novel biomarkers for diagnosis and prognosis.
Evidence snippets:
Snippet 1 (score: 0.351) > In the pregenomic eras, highly integrated and complex circuitry of molecular signaling in NPC pathogenesis was only partially understood. Over the past decade, the knowledge of the molecular mechanisms in NPC carcinogenesis has been rapidly accumulated. Dysregulation and abnormal protein expression of molecules in certain signaling pathways involved in cellular functions including proliferation, adhesion, survival, and apoptosis has been demonstrated in the NPC cells. Detailed information on the complex network in signaling pathway leading to a coordinated pattern of gene expression and regulation in NPC will undoubtedly provide important clues to develop novel prognostic and therapeutic strategies for this cancer. Refining molecular markers into clinically relevant assays may assist in the detection of NPC in asymptomatic patients, as well as stage classification and monitoring disease progression and treatments. Furthermore, selective regulation of particular proteins targeting cancer cell proliferation, invasion, and apoptosis is a hopeful prospect for future anticancer therapy that slow disease progression and improve survival.

[8] Human Dermal Fibroblast: A Promising Cellular Model to Study Biological Mechanisms of Major Depression and Antidepressant Drug Response

Authors: P. Mesdom, R. Colle, É. Lebigot, S. Trabado, Eric Deflesselle et al.
Year: 2020
Venue: Current Neuropharmacology
URL: https://www.semanticscholar.org/paper/79368e365458486de96794333613c12a6063bf54
DOI: 10.2174/1570159X17666191021141057
PMID: 31631822
PMCID: 7327943
Citations: 12
Summary: This review highlights the great and still underused potential of HDF, which stands out as a very promising tool in the understanding of MDD and AD mechanisms of action.
Evidence snippets:
Snippet 1 (score: 0.346) > Background: Human dermal fibroblasts (HDF) can be used as a cellular model relatively easily and without genetic engineering. Therefore, HDF represent an interesting tool to study several human diseases including psychiatric disorders. Despite major depressive disorder (MDD) being the second cause of disability in the world, the efficacy of antidepressant drug (AD) treatment is not sufficient and the underlying mechanisms of MDD and the mechanisms of action of AD are poorly understood. Objective The aim of this review is to highlight the potential of HDF in the study of cellular mechanisms involved in MDD pathophysiology and in the action of AD response. Methods The first part is a systematic review following PRISMA guidelines on the use of HDF in MDD research. The second part reports the mechanisms and molecules both present in HDF and relevant regarding MDD pathophysiology and AD mechanisms of action. Results HDFs from MDD patients have been investigated in a relatively small number of works and most of them focused on the adrenergic pathway and metabolism-related gene expression as compared to HDF from healthy controls. The second part listed an important number of papers demonstrating the presence of many molecular processes in HDF, involved in MDD and AD mechanisms of action. Conclusion The imbalance in the number of papers between the two parts highlights the great and still underused potential of HDF, which stands out as a very promising tool in our understanding of MDD and AD mechanisms of action

[9] Modeling psychiatric disorders: from genomic findings to cellular phenotypes

Authors: Anna Falk, Vivi M. Heine, A. Harwood, Patrick F. Sullivan, M. Peitz et al.
Year: 2016
Venue: Molecular Psychiatry
URL: https://www.semanticscholar.org/paper/235b41240d78140de7ab06a3ad8a7d0b1bdff1a5
DOI: 10.1038/mp.2016.89
PMID: 27240529
PMCID: 4995546
Citations: 77
Influential citations: 2
Summary: The challenges for modeling of psychiatric disorders, potential solutions and how iPSC technology can be used to develop an analytical framework for the evaluation and therapeutic manipulation of fundamental disease processes are critically reviewed.
Evidence snippets:
Snippet 1 (score: 0.337) > The key challenge for iPSC-based disease modeling is to identify one or more relevant cellular phenotypes that accurately represent the disease pathophysiology. Increasing numbers of reports have demonstrated that for many diseases specific pathophysiology can be captured in human iPSC-based disease models. These range from cardiovascular disease, 44,45 cancer, 46,47 ocular disease, 48,49 diabetes mellitus 50,51 and neurological disorders of the brain. 52,53 Can the same approach be applied to complex psychiatric disorders? > The problem is that almost all psychiatric disorders are characterized by clinical signs and symptoms, but lack independent verification from objective biomarkers. Thus, how might these clinical phenotypes manifest themselves in terms of cell behavior? The identity of robust cellular 'readouts', which typify any psychiatric disorder, is a crucial unsolved problem and an area of intense study 54 (Table 2). When satisfactorily answered, this will herald a new degree of biological objectivity and quantification for the study of psychiatric disorders. > The aim is to find a single or small number of cell phenotypes or parameters that strongly associate with psychiatric disorders, and establish a cellular profile characteristic of cells derived from the general patient population. Although a consensus set of cellular phenotypes for psychiatric disorder is yet to be established, we can define some of their desired characteristics. First, cellular phenotypes have to relate to the biological pathways identified by genetics. Second, although there are many risk genes in disparate biological pathways, at some level, phenotypes should converge onto a much smaller grouping. Third, phenotypes need to be quantifiable. Finally, to be useful for drug development cellular phenotypes should be reversed by pharmacological treatment, although not necessarily by drugs in current use. > Although human iPSC-based approaches underrepresent the complexity of the human central nervous system, cellular phenotypes are likely to lie more proximal to molecular disease mechanisms than phenotypes seen at the level of a tissue or organism, 55 and thus may bypass compensatory homeostatic (2) Gene expression profiles of SCZ human iPSC neurons identified altered expression of many components of the cyclic AMP and WNT signaling pathways. > (3

[10] Recent Evidences of Epigenetic Alterations in Chronic Obstructive Pulmonary Disease (COPD): A Systematic Review

Authors: R. Ragusa, Pasquale Bufano, A. Tognetti, M. Laurino, Chiara Caselli
Year: 2025
Venue: International Journal of Molecular Sciences
URL: https://www.semanticscholar.org/paper/2660cdbbe1f205c631fe890e5c6a3c8d9b81ce5f
DOI: 10.3390/ijms26062571
PMID: 40141213
PMCID: 11942187
Citations: 4
Summary: A systematic review of the latest knowledge on epigenetic modifications that characterize COPD, summarizing epigenetic factors that could serve as potential novel biomarkers and therapeutic targets for the treatment of COPD patients.
Evidence snippets:
Snippet 1 (score: 0.336) > The papers included were clustered according to epigenetic mechanisms involved in COPD (molecular and cellular processes, as biomarker or therapeutic target). Tables 4-9 describe the extracted information, including the following: Study = name of first author et al., year; Country (Region) = where the study took place; Number of participants = sample size; Type of sample = biological sample employed; Gene affected = gene or group of genes whose expression can be "regulated" by epigenetic mechanisms; Epigenetic alteration = type of epigenetic alteration observed in the presence of disease; Activity in COPD = involvement of epigenetic elements in different molecular and cellular mechanisms associated with COPD; and Role of epigenetic mechanisms = epigenetic modifications that can be used to explain the pathophysiology of COPD or as biomarkers and therapeutic targets.

[11] Chemotherapy and Mechanisms of Resistance in Breast Cancer

Authors: A. Oliveira, R. E. Santos, F. F. O. Rodrigues
Year: 2012
Venue: Unknown venue
URL: https://www.semanticscholar.org/paper/502a86d8bcd7208be6f539fcceba631f82f25a7d
DOI: 10.5772/24629
Summary: The addition of adjuvant polychemotherapy in advanced breast cancer showed gain by controlling survival of micrometastases in patients with lymph nodes affected by cancer or not.
Evidence snippets:
Snippet 1 (score: 0.336) > The main reasons responsible for treatment failure in cancer patients are the mechanisms of drug resistance and emergence of disseminated disease (Terek et al, 2003). We identified two types of resistance most relevant to BC: primary resistance, which corresponds to the clinical situation where the patient showed no response to therapy, and secondary or acquired resistance in which, initially, there is an observed response and a subsequent failure of the treatment regimen (Kroger et al, 1999). Several mechanisms may cause the phenotype of multidrug resistance to chemotherapy drugs and are well characterized in in vitro experiments, including alterations in systemic pharmacology (pharmacokinetics and metabolism), extracellular mechanisms (tumor environment, multicellular drug resistance), and cellular mechanisms (cellular pharmacology, activation and inactivation of drugs, modification of specific targets and regulatory pathways of apoptosis) (Leonessa et al, 2003, Riddick et al, 2005. Identification of factors that affect cell metabolism, which are related to drug resistance, will enable the identification of which patients are at particular risk of treatment failure. Among the biochemical and molecular mechanisms of drug resistance, we stress: changes in the activity of topoisomerase II, alterations in the DNA repair mechanism, overexpression of P-glycoprotein; high intracellular concentrations of enzymes purification of cellular metabolism -among them enzymes the family of glutathione S-transferases (GSTs) and changes in the mechanisms of signaling via c-Jun N-terminal kinase 1 (JNK1) -and "apoptosis signal-regulating kinase (ASK1) required for activation of the" mitogenactivated protein (MAP kinases) in apoptosis and cellular restoration. These pathways are also mediated by proteins encoded by genes of GSTs (O'Brien, Tew, 1996;Burg, Mulder, 2002, L'Ecuyer et al, 2004). Different response rates to particular chemotherapy regimens, as observed in patient groups with the same biological characteristics and stage, suggest the existence of different mechanisms of drug resistance, probably induced by genetic alterations (Hayes, Pulford, 1995;O'Brien , Tew, 1996;Pakunlu et al, 2003). Among the mechanisms of purification of cellular metabolism involved in the

[12] Role of Transcriptomics in Precision Oncology

Authors: Ruby Srivastava
Year: 2024
Venue: Reports of Radiotherapy and Oncology
URL: https://www.semanticscholar.org/paper/0bd862558bbb7286336111d9dfd232b5f905d3d9
DOI: 10.5812/rro-142195
Citations: 4
Summary: : Transcriptome profiling is one of the most widely used approaches in the field of multiomics research. It plays a crucial role in the prognostic, diagnostic, and predictive treatment of cancer patients. Novel next-generation sequencing (NGS) technologies permit the identification of cancer biomarkers, gene signatures, and their abnormal expression, affecting oncogenic and molecular targets and novel biomarkers for cancer therapies. Multiomics studies have changed the overall understanding o...
Evidence snippets:
Snippet 1 (score: 0.335) > : Transcriptome profiling is one of the most widely used approaches in the field of multiomics research. It plays a crucial role in the prognostic, diagnostic, and predictive treatment of cancer patients. Novel next-generation sequencing (NGS) technologies permit the identification of cancer biomarkers, gene signatures, and their abnormal expression, affecting oncogenic and molecular targets and novel biomarkers for cancer therapies. Multiomics studies have changed the overall understanding of cancer and opened a precise perspective for tumor diagnostics and therapy. The use of these approaches has strengthened our understanding of disease pathophysiology and classifications at the molecular level, including specific interference with drug mechanisms of action. Still, it has limited added value in the clinical setting. The omics data on precision medicine include the application of data from genes, transcripts, and proteins for diagnosis, monitoring of diseases, risk factor determination, counseling, and development of novel therapeutics. Bioinformatics applications have expanded statistics-based analysis toward deriving molecular pathways and process models for characterizing phenotypes and drug action mechanisms. In this review, we will discuss transcriptomics and interference analysis that allows the identification of predictive biomarkers at the molecular level to test drug response and analyze the molecular process interface of disease progression-relevant pathophysiology and mechanism of action to propose predictive biomarkers.

[13] Computational modelling of TNFα related pathways regulated by neuroinflammation, oxidative stress and insulin resistance in neurodegeneration

Authors: Hemalatha Sasidharakurup, Shyam Diwakar
Year: 2020
Venue: Applied Network Science
URL: https://www.semanticscholar.org/paper/aea95bfe3c4303f1361a8ea72828d2926ea0d03e
DOI: 10.1007/s41109-020-00307-w
Citations: 9
Summary: Simulations suggest insulin may be an important factor identifying neurodegeneration in AD and PD, through its action along with the neuroinflammation and oxidative stress.
Evidence snippets:
Snippet 1 (score: 0.335) > Modelling complex biological pathway networks including their cellular and molecular components, and interactions (Ji et al. 2017) can help connect critical factors statistically relevant as common signaling mechanisms or phentotypic functions to both disorders. Developing computational models can aid reproducing disease pathways and predicting dynamical behaviours essential for approprite protocol design and experimental testing and to map clinical symptoms to molecular processes going through cellular and circuit functions (Conradi et al. 2007;Bartocci and Lió 2016). Using biochemical systems theory (BST), sub-cellular reactions and biochemical pathways were modeled using ordinary differential equations (ODE) for reconstructing signalling dynamics in this study (Savageau et al. 1987). All biochemical reactions involved in disease-related signalling pathways were expressed mathematically using ODE and rate equations were computed using computational tools (Bartocci and Lió 2016). > The objective of this modeling exercise was to map major genes or proteins involved in disease mechanism, the reactions affected by the mutation of these genes and the difference in reactions when compared with healthy controls, action ofpotential drugs. In literature, BST models on oxidative stress and inflammation in insulin resistance were already available for PD condition (Braatz and Coleman 2015). These models explore some of the important pathways involved in PD and the treatment options. Most of the initial conditions for the model parameters were assigned as relative values rather than real data. With the need to model crosstalk and critical networks relevant to neurodegeneration identified by more recent studies, we have incorporated the crosstalk between insulin resistance, oxidative stress and neuroinflammation related to TNFα signalling in normal, AD and PD conditions (Fallahi-Sichani et al. 2011;Sasidharakurup et al. 2020;Su and Wu 2020). The parameteric values relating to biological states and initial conditions for this model were manually extracted from literature on disease models. In a previous study, we had modelled the role of TNFα mediated glutamate excitotoxicity and neuroinflammation (Sasidharakurup et al. 2020) and the variations in TNFα levels during both healthy and diseased conditions were analyzed.

[14] Targeting Hepatic Stellate Cells for the Prevention and Treatment of Liver Cirrhosis and Hepatocellular Carcinoma: Strategies and Clinical Translation

Authors: Hao Xiong, Jinsheng Guo
Year: 2025
Venue: Pharmaceuticals
URL: https://www.semanticscholar.org/paper/76e92127053136900f7e3f10e2c9278251ced5d2
DOI: 10.3390/ph18040507
PMID: 40283943
PMCID: 12030350
Citations: 8
Summary: HSC-targeted approaches using specific surface markers and receptors may enable the selective delivery of drugs, oligonucleotides, and therapeutic peptides that exert optimized anti-fibrotic and anti-HCC effects.
Evidence snippets:
Snippet 1 (score: 0.334) > Significant progress has been made in elucidating the cellular and molecular mechanisms of liver fibrosis; however, only a few findings have been successfully translated into clinical applications. Firstly, the high cost of drug development and target validation necessitates prolonged timelines and substantial financial investment. Secondly, as regulatory requirements become more stringent, there is an increasing demand for drugs with well-defined clinical efficacy and safety profiles. Moreover, the efficacy observed in animal models often fails to fully translate to clinical settings due to differences in pharmacokinetics, extracellular matrix (ECM) cross-linking, and disease pathophysiology. Despite advancements in anti-fibrotic drug development, accurately identifying ideal noninvasive biomarkers for fibrotic activity and establishing consensus on optimal clinical endpoints remain significant challenges [113,114]. > Currently, addressing the underlying cause remains the only proven strategy to halt or reverse liver fibrosis progression, while the development of effective anti-fibrotic therapies continues to pose a major challenge in liver disease management. Over the past few decades, substantial progress has been made in elucidating the cellular and molecular mechanisms underlying liver fibrosis. Liver fibrosis is a complex pathological change involving multiple cells, factors, and pathways, and the study of the cellular and molecular mechanisms of its occurrence and development provides an important theoretical basis and therapeutic target for clinical drug development. It is anticipated that improved animal models and well-designed clinical trials will facilitate the successful translation of anti-fibrotic research into effective clinical treatments in the near future.

[15] Massive changes in gene expression and their cause(s) can be a unifying principle in the pathobiology of Alzheimer's disease

Authors: P. Coleman, Elaine Delvaux, J. H. Kordower, Ashley Boehringer, Carol J. Huseby
Year: 2025
Venue: Alzheimer's & Dementia
URL: https://www.semanticscholar.org/paper/81c804d9a09df3de462ba1a9c3a1b28c98b021cd
DOI: 10.1002/alz.14555
PMID: 39912452
PMCID: 11851168
Citations: 5
Summary: Evidence for a unifying model based on sequestrations in stress granules and alteration of nucleocytoplasmic transport in AD is reviewed, with a focus on sequestrations in stress granules and alteration of nucleocytoplasmic transport.
Evidence snippets:
Snippet 1 (score: 0.333) > The Alzheimer's disease (AD) field has long been fragmented. Over the decades, there have been a series of hypotheses of biological mechanisms in AD including cholinergic (e.g., Davies & Maloney), 1 inflammation (e.g., Akiyama et al.), 2 viral, 3 mitochondrial, 4 protein processing, 5 vascular, 6 tau, 7 and amyloid 8 hypotheses, among others. > None of these hypotheses have led to halting or reversing disease, and there are a number of possible explanations for these failures, including intervention coming too late in disease progression. However, the failures do not have to mean that these hypotheses are wrong. They all deal with real facts in the biology of AD but are limited by each addressing only a portion of the biology of AD. We argue that the total biological complexity of AD is represented in the large number of changes in gene expression that have been described in many studies and represent > 90% of known Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways. The comprehensive text-mining study of Morgan et al. 9 reported that pathways altered in AD are related to synapses, cell death, inflammation, phagosome, virus infection, metabolic pathways, calcium signaling, transcription, lysosome, long-term potentiation (LTP), protein processing in endoplasmic reticulum (ER), cell cycle, actin, mammalian target of rapamycin pathway, ribosome, Ras pathway, interleukin 17 pathway, RNA polymerase RNA transport, Hippo signaling pathway, and more (see Table S9 in Morgan et al. 9 ). This raises the question of what mechanism(s) may be responsible for the thousand plus changes in gene expression in AD. > In addition to these many gene expression changes in AD, a host of risk factors have also been described for the AD clinical phenotype, including genetic, environmental, and lifestyle factors. How can we link the inputs of risk factors with the outputs of gene expression changes, AD cellular phenotype, and clinical disease? What cellular/molecular mechanism(s) may play a role in the coordinated change in expression of such large numbers of genes in AD?

[16] Microglia Activation in the Brain as Inflammatory Biomarker of Alzheimer’s Disease Neuropathology and Clinical Dementia

Authors: Z. Xiang, V. Haroutunian, L. Ho, Dushant P. Purohit, G. Pasinetti
Year: 2005
Venue: Disease Markers
URL: https://www.semanticscholar.org/paper/c67d600b340d2f12afa77ea72927ad5b491a0fca
DOI: 10.1155/2006/276239
PMID: 16410654
PMCID: 3850819
Citations: 105
Influential citations: 3
Summary: The results suggest that microglia activation increases with the progression of AD, with the increase varying depending on the involved brain region.
Evidence snippets:
Snippet 1 (score: 0.332) > In recent years, a large number of epidemiological studies have addressed the possible protective effect of anti-inflammatory drug use with regard to AD [3]. It is still uncertain however, whether inflammatory mechanisms actually cause damage in AD, or are merely present to remove the debris associated with neurodegenerative events. On a molecular level it is apparent that an inflammatory response accompanies the neu-ropathologic features of AD [1,18] though clinical features of inflammation are absent. The complement system appears to be active in the AD brain [16], with generation of the lytic membrane attack complex [24], and presumably with the release of anaphylatoxins. Upregulation of cyclooxygenase (COX)-2 in neurons as a function of the clinical progression of the AD dementia [9] suggests that inflammatory lipids may also be involved in the pathogenesis of the disease [17]. > As the major cellular mediators of inflammation, microglia have the characteristics of antigen-presenting tissue macrophages, including Human Leukocyte Antigen (HLA)-DR surface markers [11]. HLA-DR expression is found in microglia assuming either a ramified (resting state) or an amoeboid (reactive or activated state) morphology. Microglia may synthesize and secrete β-amyloid (Aβ) [26], as well as produce cytokines [25], nitric oxide and superoxide free radicals [4,5] that may aggravate or promote neurodegeneration. Activated microglia increase in AD patients and also in elderly non-AD controls [11]. Activated microglia and astrocytes have been found in abundance near neuritic plaques (NP) and neurofibrillary tangles (NT) in definitive AD cases [11,21,23]. However, it is unclear how microglia activation evolves in relation to the clinical progression of AD pathology or cognitive status. > In our previous study, we found that up-regulation of neuronal COX-2 protein appeared very early in the clinical progression of AD and preceded the onset of the induction of cytokine gene expression [9,10].

[17] Solving the Evidence Interpretability Crisis in Health Technology Assessment: A Role for Mechanistic Models?

Authors: E. Courcelles, J. Boissel, J. Massol, I. Klingmann, R. Kahoul et al.
Year: 2022
Venue: Frontiers in Medical Technology
URL: https://www.semanticscholar.org/paper/877d5b1b75599745f704a9c8371f74601ff17e2f
DOI: 10.3389/fmedt.2022.810315
PMID: 35281671
PMCID: 8907708
Citations: 6
Summary: Light is shed on different stakeholder's contributions and needs in the appraisal phase and how mechanistic modeling strategies and reporting can contribute to this effort to implement mechanistic models central in the evidence generation, synthesis, and appraisal of HTA so that the totality of mechanistic and clinical evidence can be leveraged by all relevant stakeholders.
Evidence snippets:
Snippet 1 (score: 0.332) > A second limitation in HTA is the fact that currently population (and sometimes stratified) medicine is pursued during clinical Uncertainty not completely addressed in competent authority assessment report Example use of MIDD relevant to address uncertainty potentially also during HTA What is the optimal dosage in the clinical context? > Physiologically based pharmacokinetic models can investigate dosing-regimens relevant for regulatory review and product labels (9) and can also mimic real-life adherence to prescribed treatment regimens (see also below) or pharmacology-relevant characteristics of special populations as well as drug-drug interactions. > What is the duration of the effectiveness, especially with chronic use of a treatment? > Mechanistic models can predict the long-term disease progression by extrapolation of shorter-term findings under the constraints of how the components of the system function (and these constraints convey biological plausibility by design). An example is the use of a mechanism-based disease progression model for comparison of long-term effects of pioglitazone, metformin, and gliclazide on disease processes underlying Type 2 Diabetes Mellitus (10). Another example is prediction of long-term outcomes by short-term marker data as demonstrated by a semi-mechanistic approach in context of osteoporosis treatment (11). > What is the efficacy for relevant clinical outcomes? > Mechanistic models combined with pharmacometric approaches can translate findings for one outcome to a range of other outcomes. An example of survival modeling on the back of a mechanistic description is the modeling framework for CD19-Specific CAR-T cell immunotherapy using a quantitative systems pharmacology model (12). > What is the size of the clinical effect dependent on patient characteristics and extrinsic factors? > Data-driven modeling techniques can capture correlation within clinical data. Describing the clinical effect of a drug can also be based on mechanistic considerations. Such models either (a) link disease phenotypes to increasingly granular mathematical representations of pathophysiologic processes (top-down approach) or (b) derive functional, computable cellular networks from the molecular building blocks of genes and proteins to elucidate the impact of pathologic or therapeutic alterations on network operating states and hence clinical phenotype (bottom-up) [

[18] Homocysteine thiolactone and N-homocysteinylated protein induce pro-atherogenic changes in gene expression in human vascular endothelial cells

Authors: D. Gurda, L. Handschuh, Weronika Kotkowiak, H. Jakubowski
Year: 2015
Venue: Amino Acids
URL: https://www.semanticscholar.org/paper/0e9ac31119ab67e72fdaa6e9cc442fa7ed2f4642
DOI: 10.1007/s00726-015-1956-7
PMID: 25802182
PMCID: 4458266
Citations: 93
Influential citations: 3
Summary: It is found that each Hcy metabolite uniquely modulates gene expression in pathways important for vascular homeostasis and identify new genes and pathways that are linked to HHcy-induced endothelial dysfunction and vascular disease.
Evidence snippets:
Snippet 1 (score: 0.331) > lead to the accumulation of Hcy and its metabolites in the blood-hyperhomocysteinemia (HHcy)-which is an independent risk factor for cardiovascular disease (CVD) and causes endothelial dysfunction, a hallmark of atherosclerosis (Dayal and Lentz 2008). However, molecular mechanisms underlying the pathophysiology of HHcy are not fully understood (Jakubowski 2011(Jakubowski , 2013;;Perla-Kajan et al. 2007). One hypothesis states that metabolic conversion of Hcy to Hcythiolactone initiates a pathway that leads to pathologies associated with HHcy (Jakubowski 1997a(Jakubowski , 1999(Jakubowski , 2007)). Hcy-thiolactone is chemically reactive and modifies ε-amino groups of protein lysine residues, which generates immunogenic and toxic N-homocysteinylated protein (N-Hcy-protein) (Jakubowski 2008(Jakubowski , 2013;;Jakubowski et al. 2000). > In humans and mice, HHcy leads to the accumulation of Hcy-thiolactone and N-Hcy-protein, in addition to Hcy (Chwatko et al. 2007;Jakubowski et al. 2008Jakubowski et al. , 2009)). We and other investigators have shown that HHcy induces changes in gene expression in mouse models that are associated with atherothrombotic disease (Devlin et al. 2005;DiBello et al. 2010;Ingrosso et al. 2003;Kim et al. 2011;Pogribny et al. 2008;Sharma et al. 2006;Suszynska-Zajczyk et al. 2014a, b, c, d). However, it is not known what mechanism(s) are involved and which metabolite-Hcy itself, Hcy-thiolactone, or N-Hcy-protein-is responsible for changes in gene expression. > The key to understanding mechanisms by which HHcy disrupts normal cellular function and ultimately causes disease is to identify genes whose expression is affected by individual Hcy metabolites.

[19] Differential metabolic markers associated with primary open-angle glaucoma and cataract in human aqueous humor

Authors: C. Pan, Chaofu Ke, Qin Chen, Yijin Tao, Xu Zha et al.
Year: 2020
Venue: BMC Ophthalmology
URL: https://www.semanticscholar.org/paper/a22a466f72ee8f8a5808f51c7000ff38b8b60b04
DOI: 10.1186/s12886-020-01452-7
PMID: 32375707
PMCID: 7203853
Citations: 26
Influential citations: 1
Summary: This study identified valuable metabolic biomarkers and pathways that may facilitate an improved understanding of the POAG pathogenesis and hold translational value in the development of new therapeutic measures for POAG.
Evidence snippets:
Snippet 1 (score: 0.330) > Primary open-angle glaucoma (POAG) is the most common subtype of glaucoma and the major cause of irreversible blindness throughout the world [1]. Although numerous studies have identified several important ocular risk factors for POAG such as increased intraocular pressure (IOP) [2,3], myopic refractive errors [4], larger optic disc size [5,6] and thinner central corneal thickness [7,8], these findings are limited in understanding the pathophysiology of POAG. Further knowledge regarding the pathophysiology might help to create new drug development research lines and expand current therapeutic targets for POAG. In current clinical practice, the treatment strategy of POAG mainly relies on IOP-lowering medications or surgeries. Although increased IOP is widely accepted to be the primary predictor for POAG, glaucomatous neuropathy is still observed in some patients with normal or even lower-than-normal IOPs, suggesting that other mechanisms exist in the pathophysiology of POAG. > Metabolomics is a widely used technology to assess biomarkers for diseases and provide molecular information regarding disease phenotype since metabolites are the ultimate product of gene, mRNA and protein activities [9]. Variations in the metabolome represent the interplay of genetic and environmental factors and are in relation to disease states, which may shed some lights in mechanism and pathophysiology of the disease [10]. With regard to eye diseases, metabolomics has been successfully used in identifying the metabolic signatures of diabetic retinopathy [11]. However, there were less studies focusing on POAG, especially in human participants. A previous analysis comparing plasma metabolic signatures as measured by mass spectrometry observed significant differences in some specific metabolic processes such as palmitoylcarnitine, sphingolipids, vitamin Drelated compounds, and steroid precursors between POAG patients and healthy controls [12]. These differences observed in metabolome might be linked to mitochondrial dysfunction and energy metabolism changes [12].

[20] LifeTime and improving European healthcare through cell-based interceptive medicine

Authors: N. Rajewsky, G. Almouzni, S. Gorski, S. Aerts, I. Amit et al.
Year: 2020
Venue: Nature
URL: https://www.semanticscholar.org/paper/d626a4acb560c1ef16ea394cb4dccf277882d119
DOI: 10.1038/s41586-020-2715-9
PMID: 32894860
PMCID: 7656507
Citations: 138
Influential citations: 2
Summary: The LifeTime initiative is an ambitious, multidisciplinary programme that aims to improve healthcare by tracking individual human cells during disease processes and responses to treatment in order to develop and implement cell-based interceptive medicine in Europe over the next decade.
Evidence snippets:
Snippet 1 (score: 0.328) > , a major challenge is a lack of understanding of the early events in disease onset to enable the development of disease-modifying therapies. The lack of access to longitudinal samples from patients necessitates the establishment of cohorts of patient-derived disease models to understand the cellular heterogeneity associated with disease. The discovery of pathways and biomarkers that will allow the stratification of patients on the basis of the cellular mechanisms that drive a disease will make it possible to design new clinical trials to reevaluate drugs that were previously tested without such stratification, and to broaden the drug target portfolio. > As seen during the coronavirus disease 2019 (COVID-19) pandemic, it is important to be able to understand infection mechanisms and the host response in order to rapidly identify the most likely effective treatment for an infection. At the same time, the continuous rise of antimicrobial resistance requires the discovery of new therapeutic strategies. A key medical challenge for infectious diseases is to understand the cellular response to infections and to develop precision, immune-based therapeutic strategies to combat infections. > Chronic inflammatory diseases impose a high burden owing to their long-term debilitating consequences, which result from the structural destruction of affected organs or tissues. Current therapies treat the symptoms but do not cure or fully control the chronic inflammatory pathophysiology. While different targeted therapies exist, they are expensive and their success is limited by high rates of non-response to treatment. Consequently, there is an urgent need to explore and understand how cellular heterogeneity contributes to the pathology of inflammatory diseases 61 and how this relates to the predicted course of disease and the response of a patient to one of the numerous available therapies. > Many cardiovascular and metabolic diseases lack effective therapies owing to a lack of knowledge of their underlying causes and the link between abnormal cardiac cell structure or function and pathophysiology. The identified medical priority is to understand the cellular and molecular mechanisms involved, in order to enable early diagnosis and the design of new mechanism-based therapies for precise clinical treatment. > The LifeTime disease roadmaps can be divided broadly into three phases 7 : first, immediate research into the identified medical challenges using established, scaled single-cell technologies, computational tools and disease models; second, the development of new technologies that are required

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